Autologous Platelet Concentrates in Treatment of Furcation ...

International Journal of

Molecular Sciences

Review

Autologous Platelet Concentrates in Treatment ofFurcation Defects—A Systematic Reviewand Meta-Analysis

Sourav Panda 1,2, Lorena Karanxha 1 , Funda Goker 1, Anurag Satpathy 2 , Silvio Taschieri 1,3,Luca Francetti 1,3 , Abhaya Chandra Das 2, Manoj Kumar 2, Sital Panda 4

and Massimo Del Fabbro 1,3,*1 Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano,

20122 Milan, Italy; [email protected] (S.P.); [email protected] (L.K.);[email protected] (F.G.); [email protected] (S.T.); [email protected] (L.F.)

2 Institute of Dental Science and SUM Hospital, Siksha O Anusandhan University, Bhubaneswar 751003, India;[email protected] (A.S.); [email protected] (A.C.D.); [email protected] (M.K.)

3 Dental Clinic, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy4 Department of Public Health, Regional Medical Research Center, Bhubaneswar 751003, India;

[email protected]* Correspondence: [email protected]; Tel.: +39-02-50319950; Fax: +39-02-50319960

Received: 1 February 2019; Accepted: 12 March 2019; Published: 17 March 2019��

Abstract: Background: The aim of this review was to evaluate the adjunctive effect of autologousplatelet concentrates (APCs) for the treatment of furcation defects, in terms of scientific qualityof the clinical trials and regeneration parameters assessment. Methods: A systematic search wascarried out in the electronic databases MEDLINE, SCOPUS, CENTRAL (Cochrane Central Register ofControlled Trials), and EMBASE, together with hand searching of relevant journals. Two independentreviewers screened the articles yielded in the initial search and retrieved the full-text version ofpotentially eligible studies. Relevant data and outcomes were extracted from the included studies.Risk of bias assessment was also carried out. The outcome variables, relative to baseline andpost-operative defect characteristics (probing pocket depth (PPD), horizontal and vertical clinicalattachment loss (HCAL, VCAL), horizontal and vertical furcation depth (HFD, VFD) were consideredfor meta-analysis. Results: Ten randomized trials were included in this review. Only one studywas judged at high risk of bias, while seven had a low risk, testifying to the good level of theevidence of this review. The meta-analysis showed a favorable effect regarding all outcome variables,for APCs used in adjunct to open flap debridement (p < 0.001). Regarding APCs in adjunct to bonegrafting, a significant advantage was found only for HCAL (p < 0.001, mean difference 0.74, 95% CI0.54, 0.94). The sub-group analysis showed that both platelet-rich fibrin and platelet-rich plasma inadjunct with open flap debridement, yielded significantly favorable results. No meta-analysis wasperformed for APCs in combination with guided tissue regeneration (GTR) as only one study wasfound. Conclusion: For the treatment of furcation defects APCs may be beneficial as an adjunct toopen flap debridement alone and bone grafting, while limited evidence of an effect of APCs whenused in combination with GTR was found.

Keywords: autologous platelet concentrates; bone defects; bone grafting; bone regeneration; furcationdefects; periodontal defects; periodontal regeneration; periodontal surgery; platelet-rich plasma;platelet-rich fibrin; plasma rich in growth factors; tissue healing

Int. J. Mol. Sci. 2019, 20, 1347; doi:10.3390/ijms20061347 www.mdpi.com/journal/ijms

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http://dx.doi.org/10.3390/ijms20061347

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Int. J. Mol. Sci. 2019, 20, 1347 2 of 17

1. Introduction

Furcation involvement is defined as bone resorption and attachment loss in the inter-radicularspace that results from plaque associated periodontal disease [1]. The treatment of periodontal diseaseassociated with furcation represents a challenge for the clinician, due to the complexity in anatomyand morphology of such area. The unfavorable anatomic feature of the furcation restricts adequateinstrumentation for proper debridement, thereby limiting the prognosis of the involved teeth [2].

Various treatment modalities, including surgical and non-surgical therapy, have been proposed toimprove the prognosis based on the degree of furcation involvement. Several classifications have beenproposed over the years (Table 1), based either on the severity of horizontal probing depth into thefurcation defect or on the vertical amount of alveolar bone loss within the defect [3]. The most popularone was developed by Glickman, which divides furcation defects into four grades [4]. Non-surgicalstrategies such as scaling and root planing, furcation-plasty, etc. are employed to treat the furcationswith Grade I initial involvement which restores the gingival health. Conversely, surgical proceduresincluding regenerative and resective approaches, are performed for the treatment of more advancedlesions, to allow access to the internal complex areas of furcations. The traditional resective approachmay negatively affect the long term prognosis of the treated teeth, however, it is considered as thetreatment of choice for grade III and IV furcation lesions, aiming at facilitating maintenance of thefurcation area.

Regenerative approaches are aimed at furcation closure by the formation of new bone, cementumand periodontal ligament in the involved inter-radicular space. Thorough debridement with adequateinstrumentation following surgical exposure of furcation involved area, is one of the earliest andmost well-documented treatment protocols to achieve regeneration in grade II furcation lesions [5].In addition, various studies were carried out in the recent past, using bone substitutes, barriermembrane, autologous, and recombinant growth factors in order to provide evidence of improvedbone fill and attachment gain in treating grade II furcation lesions [6,7].

The use of biologic agents consisting of growth and differentiation factors like rhBMP2(recombinant human bone morphogenetic protein-2), rhPDGF (recombinant human platelet-derivedgrowth factor), and TGF-β (transforming growth factor beta), had proven to promote osteogenicinduction in cases of furcation treatment, in animal studies [8–10]. Additionally, the use of autologousplatelet concentrates (APCs) is gaining popularity as a source of multiple growth factors in highconcentrations, for regenerative treatments in many clinical applications. The contribution ofblood-derived platelets to the bone healing process is mainly based on the growth factors storedin their granules and released upon activation. Autologous platelet concentrates are advantageouslyused as a cost-effective adjunct to surgical regenerative therapy, even in combination with bone graftsand barrier membranes. Several randomized controlled trials have reported on the efficacy of the use ofthese APCs when used alone or in combination with various regenerative strategies and other biologicagents, suggesting improvement of post-operative soft and hard tissue healing, and improved bone filland attachment gain [6,11–17]. Different types of APCs are available, each with peculiar features, themost popular being platelet-rich plasma (PRP), along with platelet-rich fibrin (PRF), plasma rich ingrowth factors (PRGF) and concentrated growth factors (CGF).

A recent systematic review and meta-analysis [18], evaluating the effect of use of platelet-richfibrin (PRF) in adjunct to open flap debridement, included two clinical trials in treatment of grade IIfurcation with nine month follow-up and concluded favorable results with the use of PRF in terms ofclinical attachment level gain (mean difference 1.25 CI 95% [0.82, 1.65], p = 0.07) and bone fill (meandifference 1.52 CI 95% [1.18, 1.87], p = 0.05). Another systematic review [19] included two split-mouthclinical trials evaluating the effect of platelet-rich plasma and reported no consistent evidence regardingthe effect of PRP in treatment of furcation defects.

The aim of this systematic review is to evaluate the adjunctive effect of APCs in treatment offurcation defects both qualitatively and quantitatively, in terms of scientific quality of the clinical trialsand regeneration parameters assessment.

Int. J. Mol. Sci. 2019, 20, 1347 3 of 17

Table 1. Various proposed classification systems of furcation involvement.

Sl Author Year Classification System

Horizontal Component

1 Goldman, H.M [20] 1958Grade I: Incipient lesion;Grade II: Cul-de-sac lesion;Grade III: Through-and-through lesion

2 Staffileno, H.J. [21] 1969

Class I: Furcations with a soft tissue lesion extending to furcal level but with aminor degree of osseous destruction;Class II: Furcations with a soft tissue lesion and a variable degree of osseousdestruction but not a through-and-through communication through the furca;Class III: Furcations with osseous destruction with through-and-throughcommunication

3 Glickman, I. [4] 1972

Grade I: Incipient lesion. Suprabony pocket and slight bone loss in thefurcation area.Grade II: Loss of interradicular bone and pocket formation but a portion of thealveolar bone and periodontal ligament remain intact.Grade III: Through-and-through lesion.Grade IV: Through-and-through lesion with gingival recession, leading to aclearly visible furcation area.

4 Hamp, S.E. et al. [22] 1975

Degree I: Horizontal attachment loss < 3 mm;Degree II: Horizontal attachment loss > 3 mm not encompassing the width ofthe furcation area;Degree III: Horizontal through-and-through destruction of the periodontaltissue in the furcation area.

5 Ramjford, S.P. et al. [23] 1979Class I: Tissue destruction < 2 mm (1/3 of tooth width) into the furcation;Class II: Tissue destruction > 2 mm (>1/3 of tooth width);Class III: Through-and-through involvement.

6 Richietti, P.A. [24] 1982

Class I: 1 mm of horizontal invasion;Class Ia. 1–2 mm of horizontal invasion;Class II: 2–4 mm of horizontal invasion;Class IIa. 4–6 mm of horizontal invasion;Class III: >6 mm of horizontal invasion.

7 Grant, D.A. et al. [25] 1988Class I: Involvement of the flute only;Class II: Involvement partially under the roof;Class III: Through-and-through loss.

8 Goldman, H.M. et al.[26] 1988

Degree I: Involves furcation entrance;Degree II: Involvement extends under the roof of furcation;Degree III: Through-and-through involvement.

9 Basaraba, N. [27] 1990Class I: Initial furcation involvement;Class II: Partial furcation involvement;Class III: Communicating furcation involvement.

10 Nevins, M. et al. [28] 1998

Class I: Incipient or early loss of attachment;Class II: A deeper invasion and loss of attachment that does not extend to acomplete invasion;Class III: Complete loss of periodontium extending from buccal to lingualsurface. Diagnosed radiographically and clinically

11 Walter, C.et al [29] 2009

Modification of the Hamp et al. classification.Degree I: Horizontal attachment loss < 1/3 of the width of the tooth;Degree II: Horizontal loss of support > 3 mm, < 6 mm;Degree II–III: Horizontal loss of support > 6 mm, but not extending completely.Degree III: Horizontal through-and-through destruction.

12 Carnevale, G. et al. [30] 2012Degree I: Horizontal attachment loss < 1/3;Degree II: Horizontal attachment loss > 1/3;Degree III: Horizontal through-and-through destruction.

Vertical Component

1 Tal, H. et al. [31] 1982

Furcal rating 1: Depth of the furcation is 0 mm;Furcal rating 2: Depth of the furcation is 1–2 mm;Furcal rating 3: Depth of the furcation is 3 mm;Furcal rating 4: Depth of the furcation is 4 mm or more.

Int. J. Mol. Sci. 2019, 20, 1347 4 of 17

Table 1. Cont.

Sl Author Year Classification System

2 Eskow, R.N. et al. [32] 1984

Furcation involvement grade 1 is classified as:Subclass A: Vertical destruction > 1/3;Subclass B: Vertical destruction of 2/3;Subclass C: Vertical destruction beyond the apical third of interradicularheight.

3 Tarnow, D. et al. [33] 1985For each class of horizontal classification (I–III), a subclass based on the verticalbone resorption was added: Subclass A: 0–3 mm; Subclass B: 4–6 mm; SubclassC: >7 mm.

Horizontal & Vertical Component (Combined)

1 Easley, J.R. et al. [34] 1969

Class I: Incipient involvement, but there is no horizontal component to thefurca;Class II: Type 1. Horizontal attachment loss into the furcation;Type 2. Vertical attachment loss into the furcation;Class III: Through-and-through attachment loss into the furcation;Type 1. Horizontal attachment loss into the furcation;Type 2. Vertical attachment loss into the furcation.

2 Fedi, P.F. [35] 1985

Glickman + Hamp classifications: Grades are the same as Glickman’sclassification (I–IV);Grade II is subdivided into degrees I and II;Degree I. Vertical bone loss 1–3 mm;Degree II. Vertical bone loss > 3 mm, but not communicatethrough-and-through.

3 Rosemberg, M.M. [36] 1986

Horizontal: Degree I: Probing < 4 mm; Degree II: Probing > 4 mm; Degree III:Two or three furcations classified as degree II are found.Vertical: Shallow: Slight lateral extension of an interradicular defect, from thecenter of the trifurcation in a horizontal direction; Deep: Internal furcationinvolvement but not penetrating the adjacent furcation.

4 Hou, G.L. et al. [37] 1998

Classification based on root trunk length and horizontal and vertical bone loss.Types of root trunk:

• Type A: Furcation involving a cervical third of root length;• Type B: Furcation involving a cervical third and two thirds of root length;• Type C: Furcation involving a cervical two thirds of root length.

Classes of furcation:

• Class I: Horizontal loss of 3 mm;• Class II: Horizontal loss > 3 mm;• Class III: Horizontal “through-and-through” loss.

Subclasses by radiographic assessment of the periapical view:

• Sub-class ‘a’. Suprabony defect;• Sub-class ‘b’. Infrabony defect.

2. Results

2.1. Study Characteristics

A total of ten studies were included in this systematic review after independent screening of titlesand abstracts from a pool of 153 articles retrieved from the search platforms. The systematic flowchart of the study selection process is provided in Figure 1. Out of 21 eligible studies, 11 studies wereexcluded with reasons provided in Table 2. The general information and the study characteristics ofthe included studies are detailed in Table 3.

The general comparison was between a group that received APC as an adjunct to surgicaltreatment (experimental group), and a group that received surgical treatment alone (control group).Three different types of comparisons were assessed, based on the treatment type. Five studies reportedthe comparison of open flap debridement (OFD) + APC versus OFD alone (Bajaj 2009 study evaluatedthe adjunctive effects of two different types of APCs in the same study, compared to OFD alone as thecontrol group). Four studies reported the comparison of bone graft (BG) + APC versus BG alone, and

Int. J. Mol. Sci. 2019, 20, 1347 5 of 17

only one study reported the comparison of guided tissue regeneration (GTR) + APC versus GTR alone.The results of these studies were separated for types of platelet concentrate data to facilitate subgroupmeta-analysis for OFD + APC versus OFD comparison. However, it was impossible to undertake thesubgroup analysis for the other two comparisons due to the lack of enough studies for sub-grouping.The risk of bias of all included studies is synthesized in Figure 2.

Int. J. Mol. Sci. 2019, 20, x 4 of 17

1 Easley, J.R. et al. [34] 1969

Class I: Incipient involvement, but there is no horizontal component to the furca; Class II: Type 1. Horizontal attachment loss into the furcation; Type 2. Vertical attachment loss into the furcation; Class III: Through-and-through attachment loss into the furcation; Type 1. Horizontal attachment loss into the furcation; Type 2. Vertical attachment loss into the furcation.

2 Fedi, P.F. [35] 1985

Glickman + Hamp classifications: Grades are the same as Glickman’s classification (I–IV); Grade II is subdivided into degrees I and II; Degree I. Vertical bone loss 1–3 mm; Degree II. Vertical bone loss > 3 mm, but not communicate through-and-through.

3 Rosemberg, M.M. [36] 1986

Horizontal: Degree I: Probing < 4 mm; Degree II: Probing > 4 mm; Degree III: Two or three furcations classified as degree II are found. Vertical: Shallow: Slight lateral extension of an interradicular defect, from the center of the trifurcation in a horizontal direction; Deep: Internal furcation involvement but not penetrating the adjacent furcation.

4 Hou, G.L. et al. [37] 1998

Classification based on root trunk length and horizontal and vertical bone loss. Types of root trunk: Type A: Furcation involving a cervical third of root length; Type B: Furcation involving a cervical third and two thirds of root length; Type C: Furcation involving a cervical two thirds of root length. Classes of furcation: Class I: Horizontal loss of 3 mm; Class II: Horizontal loss > 3 mm; Class III: Horizontal “through-and-through” loss. Subclasses by radiographic assessment of the periapical view: Sub-class ‘a’. Suprabony defect; Sub-class ‘b’. Infrabony defect.

2. Results

2.1. Study Characteristics

A total of ten studies were included in this systematic review after independent screening of titles and abstracts from a pool of 153 articles retrieved from the search platforms. The systematic flow chart of the study selection process is provided in Figure 1. Out of 21 eligible studies, 11 studies were excluded with reasons provided in Table 2. The general information and the study characteristics of the included studies are detailed in Table 3.

Figure 1. Flow chart depicting study selection process. Figure 1. Flow chart depicting study selection process.

Table 2. List of excluded studies.

Study & Year Reason for Exclusion

Mehta et al. 2018 [38] Use of Collagen Membrane along with DFDBA in control groupWanikar et al. 2018 [39] Both Control and Experimental group use PRF

Kaur et al. 2018 [40] Both Control and Experimental group use PRFSharma et al. 2017 [41] Both Control and Experimental group use PRF

Asimuddin et al. 2017 [42] Comparison between use of PRF and Allograft + GTRSalaria et al. 2016 [43] Case ReportBiswas et al. 2016 [44] Comparison between PRF and Bioactive Glass.

Pradeep et al. 2016 [45] Both Control and Experimental group uses PRFSandhu et al. 2015 [46] Case Report

Mellonig et al. 2009 [47] Histological assessmentLekovic et al. 2003 [48] Comparison of PRP/BPBM/GTR versus OFD alone

PRF—platelet-rich fibrin, PRP—platelet-rich plasma, DFDBA—de-mineralized freeze-dried allograft,BPBM—bovine porous bone mineral, GTR—guided tissue regeneration.

Table 3. Characteristics of included studies.

Study & Year StudyDesign RCT Type Treatment

ComparisonN. Defects

Test/Control Age Range GenderM/F

FollowUp

Kanoriya et al.2017 [13] RCT Parallel OFD vs. OFD + PRF 26/26 30–50 (38) 36/36 9 m

Siddiqui et al.2016 [49] RCT Parallel OFD vs. OFD + PRF 17/17 30–50 24/7 6 m

Bajaj et al.2013 [11] RCT Parallel OFD vs. OFD + PRP

OFD vs. OFD + PRF27/2727/27 39.4 22/20 9 m

Sharma et al.2011 [17] RCT Split

Mouth OFD vs. OFD + PRF 18/18 34.2 10/8 9 m

Int. J. Mol. Sci. 2019, 20, 1347 6 of 17

Table 3. Cont.

Study & Year StudyDesign RCT Type Treatment

ComparisonN. Defects

Test/Control Age Range GenderM/F

FollowUp

Pradeep et al.2009 [6] RCT Split

Mouth OFD vs. OFD + PRP 20/20 42.8 10/10 6 m

Lohi et al.2017 [14] RCT Parallel BCCG + PRF vs.

BCCG alone 10/10 25–65(43.05 + 10.73) 12/4 6 m

Lafzi et al.2013 [15] RCT Parallel ABG + PRGF vs.

ABG alone 15/15 NR NR 6 m

Mansouri et al.2012 [50] RCT Split

MouthBPBM + PRGF vs.

BPBM alone 7/7 44.7 + 11.2 4/3 6 m

Qiao et al.2017 [16] RCT Parallel BG + CGF vs. CGF

alone 15/16 NR 15/5 12 m

Jenabian et al.2017 [12] RCT Split

MouthGTR + PRGF vs.

GTR alone 8/8 NR NR 6 m

RCT—randomized clinical trial, OFD—open flap debridement, PRF—platelet-rich fibrin, PRP—platelet-rich plasma,BCCG—bioactive ceramic composite granules, ABG—autogenous bone graft, BG—bone graft, GTR—guidedtissue regeneration.Int. J. Mol. Sci. 2019, 20, x 6 of 17

Figure 2. Risk of bias (RoB) assessment.

2.2. Meta-Analysis of Primary Outcomes

2.2.1. Probing Pocket Depth (PPD)

APC + OFD vs. OFD Alone (Figure 3)

The forest plot of the included studies evaluating the change in PPD shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.59, 95% CI 1.38, 1.80). The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.46, 95% CI 1.22, 1.70) and PRP (p < 0.001, mean difference 2.09, 95% CI 1.62, 2.55).

Figure 2. Risk of bias (RoB) assessment.

Int. J. Mol. Sci. 2019, 20, 1347 7 of 17

2.2. Meta-Analysis of Primary Outcomes

2.2.1. Probing Pocket Depth (PPD)


The forest plot of the included studies evaluating the change in PPD shows evidence of anadvantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.59, 95% CI 1.38, 1.80).The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.46, 95% CI 1.22, 1.70)and PRP (p < 0.001, mean difference 2.09, 95% CI 1.62, 2.55).Int. J. Mol. Sci. 2019, 20, x 7 of 17

Figure 3. Forest plot showing the effect on probing pocket depth for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).

APC + BG vs. BG Alone (Figure 4)

The forest plot of the included studies evaluating the change in PPD in using APC in adjunct with BG favors the use of BG alone; however, the result is not statistically significant (p = 0.26, mean difference −0.08, 95% CI −0.22, 0.06).

Figure 4. Forest plot showing the effect on probing pocket depth for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).

2.2.2. Vertical Clinical Attachment Level (VCAL)


The forest plot of the included studies evaluating the change in VCAL shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.24, 95% CI 1.08, 1.40). The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.18, 95% CI 1.01, 1.36) and PRP (p < 0.001, mean difference 1.58, 95% CI 1.17, 2.00).

Study or Subgroup1.1.1 Platelet Rich Fibrin

Siddiqui 2016Bajaj 2013 aKanoriya 2017Sharma 2011Subtotal (95% CI)

Heterogeneity: Chi² = 20.83, df = 3 (P = 0.0001); I² = 86%Test for overall effect: Z = 12.08 (P < 0.00001)

1.1.2 Platelet RIch Plasma

Pradeep 2009Bajaj 2013 bSubtotal (95% CI)


Total (95% CI)

Heterogeneity: Chi² = 29.10, df = 5 (P < 0.0001); I² = 83%Test for overall effect: Z = 14.78 (P < 0.00001)Test for subgroup differences: Chi² = 5.61, df = 1 (P = 0.02), I² = 82.2%

Mean

2.274.293.69

4.056

2.33.92

SD

1.11.040.760.42

1.410.93

Total

1524231880

202545

125

Mean

1.031.582.41

2.889

0.81.58

SD

0.671.020.77

0.676

1.311.02

Total

1523241880

202343

123

Weight

10.4%12.8%23.2%32.8%79.3%

6.2%14.5%20.7%

100.0%

IV, Fixed, 95% CI

1.24 [0.59, 1.89]2.71 [2.12, 3.30]1.28 [0.84, 1.72]1.17 [0.80, 1.53]1.46 [1.22, 1.70]

1.50 [0.66, 2.34]2.34 [1.79, 2.89]2.09 [1.62, 2.55]

1.59 [1.38, 1.80]

APC + OFD OFD alone Mean Difference Mean DifferenceIV, Fixed, 95% CI

-2 -1 0 1 2Favours OFD Favours APC + OFD

Study or Subgroup

Lafzi 2013Lohi 2017Mansouri 2012Qiao 2017

Total (95% CI)

Heterogeneity: Chi² = 9.22, df = 3 (P = 0.03); I² = 67%Test for overall effect: Z = 1.12 (P = 0.26)

Mean

2.333.3753.223.48

SD

0.1981.0611.561.85

Total

1587

16

46

Mean

2.462.4

2.672.79

SD

0.2040.5160.872.07

Total

1510

716

48

Weight

94.8%3.1%1.1%1.1%

100.0%

IV, Fixed, 95% CI

-0.13 [-0.27, 0.01]0.98 [0.17, 1.78]

0.55 [-0.77, 1.87]0.69 [-0.67, 2.05]

-0.08 [-0.22, 0.06]

APC + BG BG alone Mean Difference Mean DifferenceIV, Fixed, 95% CI

-2 -1 0 1 2BG alone APC + BG


Bajaj 2013 aKanoriya 2017Sharma 2011Siddiqui 2016Subtotal (95% CI)


1.2.2 Platelet Rich Plasma

Bajaj 2013 bPradeep 2009Subtotal (95% CI)


Total (95% CI)

Heterogeneity: Chi² = 12.32, df = 5 (P = 0.03); I² = 59%Test for overall effect: Z = 15.17 (P < 0.00001)Test for subgroup differences: Chi² = 3.04, df = 1 (P = 0.08), I² = 67.1%

Mean

2.873.39

2.3332.4

2.712.5

SD

0.850.490.490.91

1.041.64

Total

2423181580

252045

125

Mean

1.372.33

1.2780.93

1.370.1

SD

0.580.48

0.4610.46

0.581.1

Total

2324181580

232043

123

Weight

15.0%33.5%26.7%9.7%

85.0%

11.6%3.4%

15.0%

100.0%

IV, Fixed, 95% CI

1.50 [1.09, 1.91]1.06 [0.78, 1.34]1.06 [0.74, 1.37]1.47 [0.95, 1.99]1.18 [1.01, 1.36]

1.34 [0.87, 1.81]2.40 [1.53, 3.27]1.58 [1.17, 2.00]

1.24 [1.08, 1.40]



Figure 3. Forest plot showing the effect on probing pocket depth for comparison of APC + OFD versusOFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in PPD in using APC in adjunctwith BG favors the use of BG alone; however, the result is not statistically significant (p = 0.26, meandifference −0.08, 95% CI −0.22, 0.06).

Int. J. Mol. Sci. 2019, 20, x 7 of 17














Total (95% CI)


Mean

2.274.293.69

4.056

2.33.92

SD

1.11.040.760.42

1.410.93

Total

1524231880

202545

125

Mean

1.031.582.41

2.889

0.81.58

SD

0.671.020.77

0.676

1.311.02

Total

1523241880

202343

123

Weight

10.4%12.8%23.2%32.8%79.3%

6.2%14.5%20.7%

100.0%

IV, Fixed, 95% CI

1.24 [0.59, 1.89]2.71 [2.12, 3.30]1.28 [0.84, 1.72]1.17 [0.80, 1.53]1.46 [1.22, 1.70]

1.50 [0.66, 2.34]2.34 [1.79, 2.89]2.09 [1.62, 2.55]

1.59 [1.38, 1.80]



Study or Subgroup


Total (95% CI)


Mean

2.333.3753.223.48

SD

0.1981.0611.561.85

Total

1587

16

46

Mean

2.462.4

2.672.79

SD

0.2040.5160.872.07

Total

1510

716

48

Weight

94.8%3.1%1.1%1.1%

100.0%

IV, Fixed, 95% CI

-0.13 [-0.27, 0.01]0.98 [0.17, 1.78]

0.55 [-0.77, 1.87]0.69 [-0.67, 2.05]

-0.08 [-0.22, 0.06]









Total (95% CI)


Mean

2.873.39

2.3332.4

2.712.5

SD

0.850.490.490.91

1.041.64

Total

2423181580

252045

125

Mean

1.372.33

1.2780.93

1.370.1

SD

0.580.48

0.4610.46

0.581.1

Total

2324181580

232043

123

Weight

15.0%33.5%26.7%9.7%

85.0%

11.6%3.4%

15.0%

100.0%

IV, Fixed, 95% CI

1.50 [1.09, 1.91]1.06 [0.78, 1.34]1.06 [0.74, 1.37]1.47 [0.95, 1.99]1.18 [1.01, 1.36]

1.34 [0.87, 1.81]2.40 [1.53, 3.27]1.58 [1.17, 2.00]

1.24 [1.08, 1.40]



Figure 4. Forest plot showing the effect on probing pocket depth for comparison of APC + BG versusBG alone at end of all-follow-up (6–12 m).



The forest plot of the included studies evaluating the change in VCAL shows evidence of anadvantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.24, 95% CI 1.08, 1.40).The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.18, 95% CI 1.01, 1.36)and PRP (p < 0.001, mean difference 1.58, 95% CI 1.17, 2.00).

Int. J. Mol. Sci. 2019, 20, 1347 8 of 17

Int. J. Mol. Sci. 2019, 20, x 7 of 17














Total (95% CI)


Mean

2.274.293.69

4.056

2.33.92

SD

1.11.040.760.42

1.410.93

Total

1524231880

202545

125

Mean

1.031.582.41

2.889

0.81.58

SD

0.671.020.77

0.676

1.311.02

Total

1523241880

202343

123

Weight

10.4%12.8%23.2%32.8%79.3%

6.2%14.5%20.7%

100.0%

IV, Fixed, 95% CI

1.24 [0.59, 1.89]2.71 [2.12, 3.30]1.28 [0.84, 1.72]1.17 [0.80, 1.53]1.46 [1.22, 1.70]

1.50 [0.66, 2.34]2.34 [1.79, 2.89]2.09 [1.62, 2.55]

1.59 [1.38, 1.80]



Study or Subgroup


Total (95% CI)


Mean

2.333.3753.223.48

SD

0.1981.0611.561.85

Total

1587

16

46

Mean

2.462.4

2.672.79

SD

0.2040.5160.872.07

Total

1510

716

48

Weight

94.8%3.1%1.1%1.1%

100.0%

IV, Fixed, 95% CI

-0.13 [-0.27, 0.01]0.98 [0.17, 1.78]

0.55 [-0.77, 1.87]0.69 [-0.67, 2.05]

-0.08 [-0.22, 0.06]









Total (95% CI)


Mean

2.873.39

2.3332.4

2.712.5

SD

0.850.490.490.91

1.041.64

Total

2423181580

252045

125

Mean

1.372.33

1.2780.93

1.370.1

SD

0.580.48

0.4610.46

0.581.1

Total

2324181580

232043

123

Weight

15.0%33.5%26.7%9.7%

85.0%

11.6%3.4%

15.0%

100.0%

IV, Fixed, 95% CI

1.50 [1.09, 1.91]1.06 [0.78, 1.34]1.06 [0.74, 1.37]1.47 [0.95, 1.99]1.18 [1.01, 1.36]

1.34 [0.87, 1.81]2.40 [1.53, 3.27]1.58 [1.17, 2.00]

1.24 [1.08, 1.40]



Figure 5. Forest plot showing the effect on vertical clinical attachment level for comparison of APC +OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VCAL in using APC in adjunctwith BG is favorable; however, the result is not statistically significant (p = 0.62, mean difference 0.06,95% CI −0.18, 0.30).

Int. J. Mol. Sci. 2019, 20, x 8 of 17

Figure 5. Forest plot showing the effect on vertical clinical attachment level for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VCAL in using APC in adjunct with BG is favorable; however, the result is not statistically significant (p = 0.62, mean difference 0.06, 95% CI −0.18, 0.30).

Figure 6. Forest plot showing the effect on vertical clinical attachment level for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).

2.2.3. Horizontal Clinical Attachment Level (HCAL)


The forest plot of the included studies evaluating the change in HCAL shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.01, 95% CI 0.89, 1.12). The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 0.93, 95% CI 0.80, 1.06) and PRP (p < 0.001, mean difference 1.50, 95% CI 1.18, 1.83).

Figure 7. Forest plot showing the effect on horizontal clinical attachment level for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in HCAL shows evidence of an advantage of using APC in adjunct with BG (p < 0.001, mean difference 0.74, 95% CI 0.54, 0.94).

Study or Subgroup


Total (95% CI)


Mean

2.543

1.652.78

SD

0.3630.9261.241.66

Total

1587

16

46

Mean

2.671.9

1.571.73

SD

0.3920.568

0.961.87

Total

15107

16

48

Weight

80.7%11.0%4.4%3.9%

100.0%

IV, Fixed, 95% CI

-0.13 [-0.40, 0.14]1.10 [0.37, 1.83]

0.08 [-1.08, 1.24]1.05 [-0.18, 2.28]

0.06 [-0.18, 0.30]









Total (95% CI)


Mean

2.752.86

2.6672.4

2.52.5

SD

0.940.0620.5941.06

0.831.17

Total

2423181580

252045

125

Mean

1.082.04

1.8890.73

1.080.8

SD

0.50.35

0.7580.46

0.50.63

Total

2324181580

232043

123

Weight

7.5%68.1%7.0%4.0%

86.6%

9.3%4.1%

13.4%

100.0%

IV, Fixed, 95% CI

1.67 [1.24, 2.10]0.82 [0.68, 0.96]0.78 [0.33, 1.22]1.67 [1.09, 2.25]0.93 [0.80, 1.06]

1.42 [1.04, 1.80]1.70 [1.12, 2.28]1.50 [1.18, 1.83]

1.01 [0.89, 1.12]


-2 -1 0 1 2OFD alone APC + OFD

Figure 6. Forest plot showing the effect on vertical clinical attachment level for comparison of APC +BG versus BG alone at end of all-follow-up (6–12 m).



The forest plot of the included studies evaluating the change in HCAL shows evidence of anadvantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.01, 95% CI 0.89, 1.12).The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 0.93, 95% CI 0.80, 1.06)and PRP (p < 0.001, mean difference 1.50, 95% CI 1.18, 1.83).

Int. J. Mol. Sci. 2019, 20, x 8 of 17

Figure 5. Forest plot showing the effect on vertical clinical attachment level for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VCAL in using APC in adjunct with BG is favorable; however, the result is not statistically significant (p = 0.62, mean difference 0.06, 95% CI −0.18, 0.30).

Figure 6. Forest plot showing the effect on vertical clinical attachment level for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).



The forest plot of the included studies evaluating the change in HCAL shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.01, 95% CI 0.89, 1.12). The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 0.93, 95% CI 0.80, 1.06) and PRP (p < 0.001, mean difference 1.50, 95% CI 1.18, 1.83).

Figure 7. Forest plot showing the effect on horizontal clinical attachment level for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in HCAL shows evidence of an advantage of using APC in adjunct with BG (p < 0.001, mean difference 0.74, 95% CI 0.54, 0.94).

Study or Subgroup


Total (95% CI)


Mean

2.543

1.652.78

SD

0.3630.9261.241.66

Total

1587

16

46

Mean

2.671.9

1.571.73

SD

0.3920.568

0.961.87

Total

15107

16

48

Weight

80.7%11.0%4.4%3.9%

100.0%

IV, Fixed, 95% CI

-0.13 [-0.40, 0.14]1.10 [0.37, 1.83]

0.08 [-1.08, 1.24]1.05 [-0.18, 2.28]

0.06 [-0.18, 0.30]









Total (95% CI)


Mean

2.752.86

2.6672.4

2.52.5

SD

0.940.0620.5941.06

0.831.17

Total

2423181580

252045

125

Mean

1.082.04

1.8890.73

1.080.8

SD

0.50.35

0.7580.46

0.50.63

Total

2324181580

232043

123

Weight

7.5%68.1%7.0%4.0%

86.6%

9.3%4.1%

13.4%

100.0%

IV, Fixed, 95% CI

1.67 [1.24, 2.10]0.82 [0.68, 0.96]0.78 [0.33, 1.22]1.67 [1.09, 2.25]0.93 [0.80, 1.06]

1.42 [1.04, 1.80]1.70 [1.12, 2.28]1.50 [1.18, 1.83]

1.01 [0.89, 1.12]



Figure 7. Forest plot showing the effect on horizontal clinical attachment level for comparison of APC+ OFD versus OFD alone at end of all-follow-up (6–12 m).

Int. J. Mol. Sci. 2019, 20, 1347 9 of 17


The forest plot of the included studies evaluating the change in HCAL shows evidence of anadvantage of using APC in adjunct with BG (p < 0.001, mean difference 0.74, 95% CI 0.54, 0.94).Int. J. Mol. Sci. 2019, 20, x 9 of 17

Figure 8. Forest plot showing the effect on horizontal clinical attachment level for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).

2.2.4. Vertical Furcation Depth (VFD)


The forest plot of the included studies evaluating the change in VFD shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.60, 95% CI 1.53, 1.68). The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.65, 95% CI 1.57, 1.74) and PRP (p < 0.001, mean difference 1.38, 95% CI 1.21, 1.56).

Figure 9. Forest plot showing the effect on vertical furcation depth for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VFD in using APC in adjunct with BG favors the use of BG alone; however, the result is not statistically significant (p = 0.90, mean difference −0.02, 95% CI −0.31, 0.27).

Figure 10. Forest plot showing the effect on vertical furcation depth for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).



Heterogeneity: Chi² = 53.23, df = 3 (P < 0.00001); I² = 94%Test for overall effect: Z = 38.43 (P < 0.00001)




Total (95% CI)


Mean

1.852.59

2.0061.93

1.771.23

SD

0.490.32

0.1630.59

0.520.43

Total

2423181580

252045

125

Mean

0.110.52

0.6220.73

0.110.64

SD

0.030.19

0.2160.46

0.030.66

Total

2324181580

232043

123

Weight

15.0%25.3%37.0%4.0%

81.3%

13.9%4.9%

18.7%

100.0%

IV, Fixed, 95% CI

1.74 [1.54, 1.94]2.07 [1.92, 2.22]1.38 [1.26, 1.51]1.20 [0.82, 1.58]1.65 [1.57, 1.74]

1.66 [1.46, 1.86]0.59 [0.24, 0.94]1.38 [1.21, 1.56]

1.60 [1.53, 1.68]



Study or Subgroup

Lafzi 2013Lohi 2017Qiao 2017

Total (95% CI)


Mean

1.261.375

2.2

SD

0.4960.5171.98

Total

158

16

39

Mean

1.60.6

1.89

SD

0.4720.6992.15

Total

151016

41

Weight

69.5%26.4%4.1%

100.0%

IV, Fixed, 95% CI

-0.34 [-0.69, 0.01]0.78 [0.21, 1.34]

0.31 [-1.12, 1.74]

-0.02 [-0.31, 0.27]



Figure 8. Forest plot showing the effect on horizontal clinical attachment level for comparison of APC+ BG versus BG alone at end of all-follow-up (6–12 m).



The forest plot of the included studies evaluating the change in VFD shows evidence of anadvantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.60, 95% CI 1.53, 1.68).The subgroup analysis is also favorable for both PRF (p < 0.001, mean difference 1.65, 95% CI 1.57, 1.74)and PRP (p < 0.001, mean difference 1.38, 95% CI 1.21, 1.56).

Int. J. Mol. Sci. 2019, 20, x 9 of 17















Total (95% CI)


Mean

1.852.59

2.0061.93

1.771.23

SD

0.490.32

0.1630.59

0.520.43

Total

2423181580

252045

125

Mean

0.110.52

0.6220.73

0.110.64

SD

0.030.19

0.2160.46

0.030.66

Total

2324181580

232043

123

Weight

15.0%25.3%37.0%4.0%

81.3%

13.9%4.9%

18.7%

100.0%

IV, Fixed, 95% CI

1.74 [1.54, 1.94]2.07 [1.92, 2.22]1.38 [1.26, 1.51]1.20 [0.82, 1.58]1.65 [1.57, 1.74]

1.66 [1.46, 1.86]0.59 [0.24, 0.94]1.38 [1.21, 1.56]

1.60 [1.53, 1.68]



Study or Subgroup


Total (95% CI)


Mean

1.261.375

2.2

SD

0.4960.5171.98

Total

158

16

39

Mean

1.60.6

1.89

SD

0.4720.6992.15

Total

151016

41

Weight

69.5%26.4%4.1%

100.0%

IV, Fixed, 95% CI

-0.34 [-0.69, 0.01]0.78 [0.21, 1.34]

0.31 [-1.12, 1.74]

-0.02 [-0.31, 0.27]



Figure 9. Forest plot showing the effect on vertical furcation depth for comparison of APC + OFDversus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VFD in using APC in adjunctwith BG favors the use of BG alone; however, the result is not statistically significant (p = 0.90, meandifference −0.02, 95% CI −0.31, 0.27).

Int. J. Mol. Sci. 2019, 20, x 9 of 17















Total (95% CI)


Mean

1.852.59

2.0061.93

1.771.23

SD

0.490.32

0.1630.59

0.520.43

Total

2423181580

252045

125

Mean

0.110.52

0.6220.73

0.110.64

SD

0.030.19

0.2160.46

0.030.66

Total

2324181580

232043

123

Weight

15.0%25.3%37.0%4.0%

81.3%

13.9%4.9%

18.7%

100.0%

IV, Fixed, 95% CI

1.74 [1.54, 1.94]2.07 [1.92, 2.22]1.38 [1.26, 1.51]1.20 [0.82, 1.58]1.65 [1.57, 1.74]

1.66 [1.46, 1.86]0.59 [0.24, 0.94]1.38 [1.21, 1.56]

1.60 [1.53, 1.68]



Study or Subgroup


Total (95% CI)


Mean

1.261.375

2.2

SD

0.4960.5171.98

Total

158

16

39

Mean

1.60.6

1.89

SD

0.4720.6992.15

Total

151016

41

Weight

69.5%26.4%4.1%

100.0%

IV, Fixed, 95% CI

-0.34 [-0.69, 0.01]0.78 [0.21, 1.34]

0.31 [-1.12, 1.74]

-0.02 [-0.31, 0.27]



Figure 10. Forest plot showing the effect on vertical furcation depth for comparison of APC + BGversus BG alone at end of all-follow-up (6–12 m).

Int. J. Mol. Sci. 2019, 20, 1347 10 of 17

2.2.5. Horizontal Furcation Depth (HFD)


The forest plot of the included studies evaluating the change in HFD shows evidence ofan advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.13, 95% CI 0.85,1.41).No subgroup analysis was carried out for this outcome due to the lack of enough studies.

Int. J. Mol. Sci. 2019, 20, x 10 of 17



The forest plot of the included studies evaluating the change in HFD shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.13, 95% CI 0.85,1.41). No subgroup analysis was carried out for this outcome due to the lack of enough studies.

Figure 11. Forest plot showing the effect on horizontal furcation length for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VFD shows evidence of an advantage of using APC in adjunct with BG (p = 0.02, mean difference 0.17, 95% CI 0.02, 0.31).

Figure 12. Forest plot showing the effect on horizontal furcation length for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).

3. Discussion

The use of platelet concentrates to promote periodontal regeneration has gained popularity in the last 10 years, as demonstrated by the increasing number of evidence-based randomized studies and systematic reviews [19,51,52]. A recent Cochrane systematic review [53] investigated the effect of APC for the surgical treatment of infrabony defects, reporting positive effects when APC is used in combination with OFD, OFD + BG, but not with GTR and enamel matrix derivative. The latter two treatments have a predictable and well-documented efficacy, and they are since long considered the gold standard for periodontal defects, so it can be difficult for any adjunctive therapy to further enhance the clinical outcomes. Evidence-based studies on the efficacy of APC for the regeneration therapy of furcation defects are relatively scarce as compared to infrabony defects. Our systematic review published in 2011 investigated the effects of APC on infrabony defects, gingival recessions and furcation defects but found only two studies on the latter topic, both using platelet-rich plasma [19]. The present study is the first comprehensive systematic review that was aimed at exploring and comparing the effect of various APCs for enhancing furcation treatment. It was designed according to a standard protocol, aimed at selecting only the best evidence studies, so as to provide the most reliable results. Only one of the ten included studies was judged at high risk of bias [50], while seven had a low risk, testifying to the good level of the evidence of this review. The results, derived from the analysis of different clinical outcome variables, suggested that the use of APC may be beneficial for improving the regeneration of furcation defects, when associated with OFD, in line with the above

Study or Subgroup

Pradeep 2009Siddiqui 2016

Total (95% CI)


Mean

1.332.13

SD

0.930.52

Total

2015

35

Mean

0.091.07

SD

0.480.46

Total

2015

35

Weight

37.0%63.0%

100.0%

IV, Fixed, 95% CI

1.24 [0.78, 1.70]1.06 [0.71, 1.41]

1.13 [0.85, 1.41]



Study or Subgroup


Total (95% CI)


Mean

12

2.51

SD

0.1740.756

2.18

Total

158

16

39

Mean

0.871.11.3

SD

0.2260.876

2.47

Total

151016

41

Weight

95.7%3.5%0.8%

100.0%

IV, Fixed, 95% CI

0.13 [-0.01, 0.27]0.90 [0.15, 1.65]

1.21 [-0.40, 2.82]

0.17 [0.02, 0.31]



Figure 11. Forest plot showing the effect on horizontal furcation length for comparison of APC + OFDversus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VFD shows evidence ofan advantage of using APC in adjunct with BG (p = 0.02, mean difference 0.17, 95% CI 0.02, 0.31).

Int. J. Mol. Sci. 2019, 20, x 10 of 17



The forest plot of the included studies evaluating the change in HFD shows evidence of an advantage of using APC in adjunct to OFD (p < 0.001, mean difference 1.13, 95% CI 0.85,1.41). No subgroup analysis was carried out for this outcome due to the lack of enough studies.

Figure 11. Forest plot showing the effect on horizontal furcation length for comparison of APC + OFD versus OFD alone at end of all-follow-up (6–12 m).


The forest plot of the included studies evaluating the change in VFD shows evidence of an advantage of using APC in adjunct with BG (p = 0.02, mean difference 0.17, 95% CI 0.02, 0.31).

Figure 12. Forest plot showing the effect on horizontal furcation length for comparison of APC + BG versus BG alone at end of all-follow-up (6–12 m).

3. Discussion

The use of platelet concentrates to promote periodontal regeneration has gained popularity in the last 10 years, as demonstrated by the increasing number of evidence-based randomized studies and systematic reviews [19,51,52]. A recent Cochrane systematic review [53] investigated the effect of APC for the surgical treatment of infrabony defects, reporting positive effects when APC is used in combination with OFD, OFD + BG, but not with GTR and enamel matrix derivative. The latter two treatments have a predictable and well-documented efficacy, and they are since long considered the gold standard for periodontal defects, so it can be difficult for any adjunctive therapy to further enhance the clinical outcomes. Evidence-based studies on the efficacy of APC for the regeneration therapy of furcation defects are relatively scarce as compared to infrabony defects. Our systematic review published in 2011 investigated the effects of APC on infrabony defects, gingival recessions and furcation defects but found only two studies on the latter topic, both using platelet-rich plasma [19]. The present study is the first comprehensive systematic review that was aimed at exploring and comparing the effect of various APCs for enhancing furcation treatment. It was designed according to a standard protocol, aimed at selecting only the best evidence studies, so as to provide the most reliable results. Only one of the ten included studies was judged at high risk of bias [50], while seven had a low risk, testifying to the good level of the evidence of this review. The results, derived from the analysis of different clinical outcome variables, suggested that the use of APC may be beneficial for improving the regeneration of furcation defects, when associated with OFD, in line with the above

Study or Subgroup

Pradeep 2009Siddiqui 2016

Total (95% CI)


Mean

1.332.13

SD

0.930.52

Total

2015

35

Mean

0.091.07

SD

0.480.46

Total

2015

35

Weight

37.0%63.0%

100.0%

IV, Fixed, 95% CI

1.24 [0.78, 1.70]1.06 [0.71, 1.41]

1.13 [0.85, 1.41]



Study or Subgroup


Total (95% CI)


Mean

12

2.51

SD

0.1740.756

2.18

Total

158

16

39

Mean

0.871.11.3

SD

0.2260.876

2.47

Total

151016

41

Weight

95.7%3.5%0.8%

100.0%

IV, Fixed, 95% CI

0.13 [-0.01, 0.27]0.90 [0.15, 1.65]

1.21 [-0.40, 2.82]

0.17 [0.02, 0.31]



Figure 12. Forest plot showing the effect on horizontal furcation length for comparison of APC + BGversus BG alone at end of all-follow-up (6–12 m).

3. Discussion

The use of platelet concentrates to promote periodontal regeneration has gained popularity inthe last 10 years, as demonstrated by the increasing number of evidence-based randomized studiesand systematic reviews [19,51,52]. A recent Cochrane systematic review [53] investigated the effectof APC for the surgical treatment of infrabony defects, reporting positive effects when APC is usedin combination with OFD, OFD + BG, but not with GTR and enamel matrix derivative. The lattertwo treatments have a predictable and well-documented efficacy, and they are since long consideredthe gold standard for periodontal defects, so it can be difficult for any adjunctive therapy to furtherenhance the clinical outcomes. Evidence-based studies on the efficacy of APC for the regenerationtherapy of furcation defects are relatively scarce as compared to infrabony defects. Our systematicreview published in 2011 investigated the effects of APC on infrabony defects, gingival recessions andfurcation defects but found only two studies on the latter topic, both using platelet-rich plasma [19].The present study is the first comprehensive systematic review that was aimed at exploring andcomparing the effect of various APCs for enhancing furcation treatment. It was designed accordingto a standard protocol, aimed at selecting only the best evidence studies, so as to provide the mostreliable results. Only one of the ten included studies was judged at high risk of bias [50], while sevenhad a low risk, testifying to the good level of the evidence of this review. The results, derived from theanalysis of different clinical outcome variables, suggested that the use of APC may be beneficial forimproving the regeneration of furcation defects, when associated with OFD, in line with the above

Int. J. Mol. Sci. 2019, 20, 1347 11 of 17

findings regarding infrabony defects. Further, it may be noted that APC in adjunct to OFD + BG alsoshowed significant improvement in HCAL and HFL. Since only one RCT evaluated the adjunctiveeffect of APC when using GTR for grade II furcation defects, no meta-analysis was feasible. The resultsof this study, suggested that the adjunct of APC produced no significant advantage as compared toGTR alone, in line with previous findings for infrabony defects.

This review has some strengths and limitations. In recent years, there has been fierce competitionamong companies producing different types of platelet concentrates, all claiming that their productwas superior to the others. This also introduced a number of different protocols for the preparationof APC. Indeed, very few studies comparing different types of APC have been performed in theperiodontal field (as well as in other fields), so that it seems difficult to indicate if there is reallya superiority of some APCs over the others for specific conditions. In the present review, we wereable to perform a meta-analysis with subgroups, keeping separate different APC (PRP and PRF), onlyin the group considering OFD alone. The outcomes using different APC was very similar as can beseen in Figures 3–6 This can be considered a strong point of the present review. However, the precisedifference in effects between different APC cannot be estimated, due to a lack of direct comparisons.The same subgroup analysis could not be performed in the OFD + BG group, due to heterogeneityamong studies in the type of APC used, and the insufficient number of studies using the same typeof APC. Indeed, also when different studies use the same type of APC, this does not necessarilyrepresent a warranty of homogeneity in the protocols. For example, over 20 different types of devicesproducing PRP are currently available on the market, and at least five different companies producecentrifuges for PRF [54]. A recent in vitro study compared the characteristics of PRF obtained usingfour different centrifuge systems [55]. This study found that, even though in all cases a leukocyte- andplatelet-rich fibrin is obtained after centrifugation, the centrifuge characteristics and centrifugationprotocols significantly impact the cell composition and distribution, the growth factors release patternand the fibrin architecture of the final products. So, when PRF is used in different studies, one cannotbe sure to refer to a product with the same features, unless the same centrifuge system is used. In spiteof the above limitations, caused by lack of homogeneity in study protocols, it can be noted that allstudies investigating the effect of APC as an adjunct to OFD alone, consistently reported a beneficialeffect. The latter can be considered a strength point evidenced by this review.

In addition to the regenerative properties, platelet concentrates have also been demonstrated tocarry further advantages in the postsurgical healing period. Evidence-based studies in different oralsurgery procedures have reported that the adjunctive use of APC is associated with an improvementof patients’ quality of life and pain reduction in the post-surgical period [56,57] Unfortunately, sucheffects were not consistently addressed in the studies included in the present review.

Finally, though specific clinical studies have not been performed so far, there is consistentpreclinical evidence that APCs have an antimicrobial effect against a number of species commonlyfound in the oral cavity, which suggest they may potentially represent a beneficial tool for the control ofpostsurgical infection [58,59]. Indications for future research: There is a huge demand for conductingmore evidence-based comparative studies with wide sample size (among different APC and graftingmaterials and versus other biological agents), to investigate patients’ quality of life, to treat variousgrades of furcation, in order to verify the actual beneficial effects of use of APC as adjunct with widevariety of regenerative strategies.

4. Material and Methods

This systematic review and meta-analysis were carried out based on preferred reporting items forsystematic reviews and meta-analysis (PRISMA) guidelines. The protocol of this systematic reviewwas registered on the international prospective register of systematic reviews (PROSPERO) withregistration number CRD42019100015.

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4.1. Research Question

What is the effectiveness of autologous platelet concentrates used as an adjunct to differenttypes of surgical techniques for the treatment of furcation defects, compared to the same surgicaltechniques alone?

4.2. Search Strategy

A systematic digitalized search was carried out in the following electronic databases: MEDLINE,SCOPUS, CENTRAL (Cochrane Central Register of Controlled Trials), and EMBASE, using a series ofsearch terms combined with the Boolean Operators “AND”, “OR”, and “NOT”. The following searchstring was developed with the combination of relevant keywords: “(((Furcation Defects) OR FurcationInvolvement)) AND (((((((Platelet Concentrates) OR Platelet-rich plasma) OR Platelet-rich fibrin) ORGrowth factors) OR PRP) OR L-PRF) OR CGF)”. The last electronic search was carried out in October2018. In addition, a hand search was performed in the following dental journals: British Dental Journal,British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research,Clinical Oral Implants Research, Clinical Oral Investigations, European Journal of Oral Implantology,European Journal of Oral Sciences, Implant Dentistry, International Journal of Oral and MaxillofacialImplants, International Journal of Oral and Maxillofacial Surgery, International Journal of Periodonticsand Restorative Dentistry, Journal of Clinical Periodontology, Journal of Dental Research, Journal ofDentistry, Journal of Implantology, Journal of Maxillofacial and Oral Surgery, Journal of Oral andMaxillofacial Surgery, Journal of Periodontal Research, Journal of Periodontology, and Oral Surgery,Oral Medicine, Oral Pathology, Oral Radiology. The reference citations of the eligible studies and othersystematic reviews were also searched for possible additional eligible studies. Finally, the online trialregistries were also searched for any ongoing studies: US National Institutes of Health Ongoing TrialsRegister ClinicalTrials.gov (clinicaltrials.gov; searched 20 October 2018); World Health OrganizationInternational Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 20 October 2018).No language restrictions were applied.

4.3. Inclusion Criteria

The criteria for the articles to be included in this present systematic review were as follows:

• Randomized clinical trials (RCT), either of a parallel group or of a split-mouth design;• Presence of at least one experimental group in which APCs were clinically applied as an adjunct

to surgical procedures alone or in combination with bone grafting materials or GTR proceduresfor the therapy of furcation defects;

• Presence of an appropriate control group, in which the same therapeutic procedures as thoseemployed in at least one experimental group were clinically applied for the treatment of furcationdefects, without the adjunctive effect of APCs;

• Patients included in the RCT should present with maxillary/mandibular Grade 2 or 3furcation defects;

• Patients included in the RCT should have no systemic diseases nor taking medications that couldpotentially influence the outcome of periodontal therapy;

• The follow-up period had to be at least 6 months.

4.4. Selection of Studies

Following the electronic search in all the respective databases, the records were imported intoEndNote 13 software (EndNoteX3; Thomas Reuters, New York, NY, USA) and the duplicates weresorted to be removed from the pool of titles. A total of 153 titles and abstracts (if available) wereindependently screened by two reviewers (MDF, SP) to exclude all articles clearly not meeting theinclusion criteria. Of all the eligible articles, full texts were obtained and were thoroughly assessed.

clinicaltrials.gov

apps.who.int/trialsearch

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Only articles fulfilling the inclusion criteria were considered. In cases of disagreement between the tworeviewers, a third reviewer (LF) was consulted. Detailed reasons were stated for all excluded studies.

4.5. Data Extraction and Management

The relevant data of the included studies were extracted using an Excel spreadsheet (Microsoft,Radmond, WA, USA). Data were independently extracted by two review authors (MDF, FG) andrecorded on predetermined spreadsheets. In case of missing or unclear information, the authors of theincluded studies were contacted by email for providing clarification or missing information.

The following data were recorded for each included report:

• Patients’ demographic characteristics• Study design and sample size• Type of platelet concentrate used (PRP, PRF, PRGF, CGF)• Follow up duration• source of funding and study setting• Outcome variables, relative to baseline and post-operative defect characteristics (probing pocket

depth (PPD), horizontal and vertical clinical attachment loss (HCAL, VCAL), horizontal andvertical furcation depth (HFD, VFD)

4.6. Risk of Bias Assessment

Risk of Bias was assessed by two independent reviewers (ACD, AS) for all the included clinicaltrials and the discrepancies were resolved by discussion and in consent with a third reviewer (MK). Thedomains of the study were graded under high, unclear or low risk, based on the following categories:Selection bias (random sequence generation and allocation concealment), performance bias (blinding),detection bias (assessor blinding), attrition bias (incomplete outcome data), reporting bias (selectivereporting), sample size calculation and number of surgeons involved. Based on the domains, thestudies categorized as low risk of bias if all domains were at low risk; high risk of bias if two or moredomains were at high risk; or medium risk of bias if one domain were at unclear or high risk.

4.7. Data Synthesis

Data of the various outcomes were extracted from each included study. Parallel group andsplit-mouth studies were combined in the meta-analysis of treatment effects. For all the outcomes,mean differences and 95% confidence interval (CI) were used to summarize the results for eachincluded study. The meta-analysis was performed using Review Manager 5.3 software (RevMan 5.3,Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) usingthe fixed or random effects models, as appropriate. Fixed effects meta-analysis was used when theheterogeneity was small (i2 < 60%, p > 0.05). When the heterogeneity was large (i2 > 60%, p < 0.05),a random-effects model analysis was undertaken.

5. Conclusions

In conclusion, the evidence available in the literature for the beneficial effects of plateletconcentrates in periodontal furcation defects has been increasing in recent years. Platelet-rich plasmaand platelet-rich fibrin may be advantageously used as an adjunct to open flap debridement aloneand additional grafting procedures, while there is no evidence of an effect of APC when used incombination with GTR, for the treatment of furcation defects.

Author Contributions: S.P. (Sourav Panda), M.D.F. and L.F. designed and conducted the search strategy, M.D.F.,F.G. and L.K. did the selection of studies and data extraction, S.P. (Sourav Panda) and S.P. (Sital Panda) performedand interpreted the meta-analysis, A.C.D., A.S. and M.K. carried out the risk of bias assessment. S.P. (SouravPanda) and M.D.F. drafted the manuscript. The final version of the manuscript was read and approved byall authors.

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Funding: This research received no external funding.

Acknowledgments: We would like to thank IRCCS Istituto Ortopedico Galeazzi for supporting us with thepublication cost of this work.

Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

APCs Autologous platelet concentratesPPD Probing pocket depthHCAL Horizontal clinical attachment lossVCAL Vertical clinical attachment lossHFD Horizontal furcation depthVFD Vertical furcation depthGTR Guided tissue regenerationrhBMP2 Recombinant human bone morphogenetic protein-2rhPDGF Recombinant human platelet-derived growth factorTGF-β Transforming growth factor betaPRP Platelet-rich plasmaPRF Platelet-rich fibrinPRGF Plasma rich in growth factorsCGF Concentrated growth factorsPRISMA Preferred reporting items for systematic reviews and meta-analysisRCT Randomized clinical trialsCI Confidence intervalOFD Open flap debridementBG Bone graft

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